RESEARCH: CANCER
FOLDING PROJECT #18921 PROFILE

Lasso peptides are unique molecules with potential for new drugs. This project uses computer simulations to understand how lasso peptides form their special shape and how they create the link that makes them work. This could lead to new treatments for diseases.

Note: This TLDR is a simplication and may not be 100% accurate.

Lasso peptides are ribosomally synthesized and post-translationally modified peptide (RiPP) natural products that display a unique lariat-like, threaded conformation.

Some lasso peptides have been shown to bind human cell-surface receptors and exhibit anticancer properties, while others display antibacterial or antiviral bioactivities.

So studies on the lasso peptide synthesis will significantly facilitate the discovery and application of new drugs. Specifically, previous studies show that the unique lasso topology is formed by a macrolactam ring that is threaded by the C-terminal tail.

While not proven yet, the threading cannot occur after the ring formation.

The general proposed mechanism is that lasso peptide first form a prefolded lariat-like structure, then lasso peptide cyclase catalyzes the ring closure achieved by an isopeptide bond formed between the N-terminal α-amino group of a glycine, alanine, serine, or cysteine and the carboxylic acid side chain of an aspartate or glutamate, which can be located at positions 7, 8, or 9 of the amino acid sequence.

However, MD study on lasso peptide topology is very less and the detailed function of lasso peptide cyclase and the molecular mechanism of the whole lasso peptide cyclization process are not clear.

Therefore, in this study, we will perform Molecular Dynamic simulations for the system of lasso peptide or peptide with cyclase enzyme to explore lasso peptide topology and the cyclization mechanism.

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Lasso peptides

Ribosomally synthesized and post-translationally modified peptide (RiPP) natural products with a unique lariat-like conformation.

Lasso peptides are a type of naturally occurring molecule produced by ribosomes. They have a distinctive loop structure and can bind to various cellular targets, making them interesting for drug development.

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RiPP

Ribosomally synthesized and post-translationally modified peptides

RiPP stands for Ribosomally Synthesized and Post-Translationally Modified Peptides. These are natural molecules produced by ribosomes and further modified after their synthesis.

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Macrolactam ring

A cyclic amide formed by the reaction between a carboxylic acid and an amine group within the same molecule.

A macrolactam ring is a large ring structure created when a carboxylic acid group reacts with an amine group within the same molecule. This type of ring is found in lasso peptides.

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Isopeptide bond

A peptide bond formed between the side chain carboxyl group of one amino acid and the side chain amino group of another amino acid.

An isopeptide bond is a special type of chemical link that joins two amino acids. Unlike a typical peptide bond, it connects the side chains (R groups) rather than the main chain.

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Molecular Dynamic simulations

Computer simulations used to model the movement and interactions of atoms and molecules over time.

Molecular Dynamic simulations are computer programs that mimic how atoms and molecules behave. They can be used to study things like protein folding or drug interactions.

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Cyclization

The process of forming a ring structure.

Cyclization is the chemical process of creating a ring-shaped molecule. It's important in biology because many natural compounds have rings.